Glaucoma is a human disorder marked by progressive loss of vision; it is one of the leading causes of irreversible blindness in the world. The World Health Organization (WHO) estimated that the total number of glaucoma cases was 105 million people in 1977. In China alone, Foster and Johnson in 2001 reported that the disease afflicted an estimated 9.4 million people (for age group 40 years and older), of which 5.2 million (55%) were blind in at least one eye.
One hypothesis underlying the loss of retinal ganglion cells in glaucoma is the induction of cell death genes either because of blockage of retrograde axonal transport or increase production of toxic material in the eye. Thus, the objective of the experiment is to make use of our established animal model of glaucoma with increased intraocular pressure by blocking the outflow of the aqueous humour with laser photocoagulation of the episcleral and limbal veins. In addition, our previous work has shown that lithium chloride is a neuroprotective factor in the eye. LiCl or other photosensitive lithium compounds has been injected into rats to examine their role in protecting the death of retinal ganglion cells in the rat glaucoma model. This model is useful in studying the mechanism of lithium on preventing cell death in glaucoma. The photosensitive lithium compounds have much lower side effect since it would only be activated inside the eye, so this approach is potentially be useful for patients with the glaucoma disease.
The major pathological features of glaucoma are the death of retinal ganglion cells (RGSs), and cupping and atrophy of optic nerve head leading to the loss of vision. (Leske, 1983; Osborne, 1999; Quigley, 1979). Glaucomatous optic neuropathy reduces vision gradually and often without symptoms. Many patients are unaware of the pathological condition during the early stage of glaucoma until it progresses into complete blindness. Similar to other neurons in the central nervous system (CNS), RGCs do not generally regenerate once they are damaged. However, progressive visual field loss in many types of eye diseases affecting the RGC axons can be prevented if it is treated at an early stage. Therefore, it is important to prevent the degeneration of RGCs in any kind of optic neuropathy.
So far, there seems to be no adequate therapy for protecting against the death of the retinal ganglion cells in glaucoma. The current clinical treatment for glaucoma is to delay the progressive loss of RGCs with the few neuroprotective agents available, while much research effort is directed towards the prevention of RGC death and apoptosis in various optic neuropathy conditions. Knowledge of the mechanisms responsible for the various optic neuropathy conditions such as glaucomatous optic neuropathy, ischemic optic neuropathy, inflammatory optic neuropathy, compressive optic neuropathy and traumatic optic neuropathy, is critical in the development of new treatments for them. A number of animal glaucoma models have been established to mimic the pathogenic conditions including optic nerve transection (Cheung, 2002; Cho, 1999; Cho, 2001; Lu, 2003; You, 2002), and ocular hypertension (Garcia-Valenzuela, 1995; Laquis, 1998; McKinnon, 2002; Mittag, 2000; Morrison, 1997; Sawada, 1999; Ueda, 1998). The present inventors have developed an ocular hypertensive model of photocoagulation to the limbal and episcleral veins using argon laser (Ji, 2004; WoldeMussie, 2001; WoldeMussie, 2002).
Lithium chloride is a common drug for the clinical treatment of mania and depression. Recent studies suggest that it has a neuroprotective effect on the injured CNS via a number of intracellular signaling pathways including upregulation of the anti-apoptotic gene Bcl-2, and inhibition of glycogen synthase kinase-3β (GSK-3β). Lithium-induced Bcl-2 upregulation plays a pivotal role in neuroprotection against glutamate excitotoxicity and supporting the intrinsic growth potential of injured axons. GSK-3β is a key downstream target of the PI3-kinase/Akt signaling pathway that regulates apoptosis in the injured CNS. Using the ocular hypertensive model to study the pathophysiology of glaucoma, So and his colleagues have shown that lithium chloride could prevent degeneration of RGC (Ji, 2002).
Despite the immense therapeutic value of lithium, there are serious long-term associated complications. These include severe, coarse tremor, exacerbation of dermatological disorders, leukocytosis, hypothyroidism, hypoparathyroidism as well as disruption of kidney function (Birch, 1999 and 1999). The undesirable side effects are possibly caused by slow penetration of lithium through the blood-brain barrier and across other membranes, resulting in delayed onset of action which necessitates the high dosage (Shanzer, 1983). Accordingly, it is an object of the current invention to provide new treatments and methods utilizing the novel use of photosensitive compounds to treat various diseases.
Photosensitive systems, including those with photochromic units such as diazene or chromene, have been widely used in unrelated fields such as optical recording and information storage devices (Ishige, 1980; Loerincz, 2003; Matsui, 1994), light-controlling media (Levy, 1997; Natansohn, 1999; Nunzi, 1996), liquid crystal displays and organic light-emifting devices (Shinbo, 2002; Zhang X. H., 2001), molecular switches (Ikeda, 2000; Yoon, 2003; Zhang Zhihua, 2003) as well as security inks for anti-forgery trademarks (Fan, 1997). More particularly, the photoresponsive system described in this invention includes a photosensitive moiety attached to or incorporated in a chelating moiety; such photoresponsive chelators have been used for sensing (Alward, 1998; Rompotis, 2002) and extraction of metal ions (Alward, 1998; Blank, 1981; Shinkai, 1980; Shinkai, 1981).